Diabetes affects an estimated 15 million people in the United States. Within the diabetic population are individuals with chronic, non-healing lower extremity ulceration (LEU), which is associated with significant morbidity and treatment costs. Chronic, non-healing LEU precedes about 85% of the lower extremity amputations (LEA) that over 50,000 diabetics experience annually (GE Reiber, E J Boyko, D G Smith, in Diabetes in America, NIH Publication No. 95-1468, Bethesda, Md., ed. 2, 1995, pp. 409-428). This represents more than half of all individuals receiving LEA in this country. While only 6% of diabetic hospitalizations are associated with LEU, the total government reimbursement for diabetic lower extremity complications in 1992 exceeded $1.5 billion, not including costs for limb amputation and rehabilitation. Clinical pathophysiologic risk factors for LEA include diabetic neuropathy, lower extremity ischemia, and chronic, non-healing diabetic foot ulcers.
The underlying problem in diabetics with LEU is impaired wound healing, which is poorly understood. While the majority of diabetics exhibit "normal" wound healing, those presenting with chronic LEU often demonstrate decreased wound inflammation, recurrent wound infections, decreased cutaneous vascular perfusion, poor wound collagen deposition, and scar maturation. Platelet derived growth factor (PDGF) deficiency is associated with the chronic diabetic ulcer and contributes to impaired healing (H D Beer, M T Longaker, S Werner, J Invest Dermatol 109, 132 (1997)). Clinical trials using Regranex.RTM. have shown efficacy in improving chronic foot ulcer healing in only half or less of the patients evaluated (D L Steed, J Vasc Surg, 21, 71 (1995)).
Recent research on the role of nitric oxide (NO) in wound inflammation, tissue repair, and microvascular homeostasis has allowed us to consider NO as a primary regulator of wound healing (D Bruch-Gerharz, T Ruzicka, V Kolb-Bachofen. J Invest Dennatol. 110, 1 (1998); M R Schaffer et al., Surgery 121, 513 (1997)). A systemic deficiency of endothelial-derived NO has been observed in all diabetics (A Veves et al., Diabetes, 47, 457 (1998); M Huszka et al., Thrombosis Res, 86(2), 173 (1997); S B Williams, J A Cusco, M A Roddy, M T Hohnston, M A Creager, J. Am. Col. Cardiol., 27(3), 567 (1996)), suggesting that NO plays a fundamental role in the pathogenesis of chronic, non-healing LEU. Consequently, there is a need to correlate NO production with wound healing ability in diabetics. Such a correlation would allow the development of methods to predict the wound healing ability of diabetics based on their production of NO and would provide a useful clincal indicator which could serve as a basis for choosing appropriate therapy.